Cancer is one of the leading causes of death in the United States. The American Cancer Society reports that about 494,000 people died from cancer in the United States in 1988. A common method of treatment for cancer is the use of chemotherapy. The use of chemotherapy has not been particularly successful in the treatment of solid tumors. Accordingly, there is a substantial need for new drugs which are effective in inhibiting the growth of such tumors.
It has now been found that a new group of furanoindolines have been effective in inhibiting the growth of solid tumors.
CC-1065 is an antitumor antibiotic that was isolated from the fermentation cultures of Streptomyces zelensis in 1978. See Martin, et al., J. Antibiot. 1981, 34, 1119; Martin, et al., J. Antibiot. 1980, 33, 902; Hanka, et al., J. Antibiot. 1978, 31, 1211. This molecule is an exceptionally potent cytotoxic agent that binds covalently to the minor groove of double stranded DNA and has good in vitro and in vivo pharmacology. For a review of the chemistry, biosynthesis, pharmacology and toxicology of CC-1065, see Reynolds, et al., J. Antibiot. 1986, 39, 319; Hurley, et al., Acc. Chem. Res. 1986, 19, 230.
Unfortunately administration of a single intravenous subtherapeutic dose of CC-1065 led to delayed deaths of healthy mice as a result of the hepatotoxicity of this molecule. McGovren, et al., J. Antibiot. 1984, 37, 63. This preempted the clinical development of CC-1065, but synthesis of fragments and analogs of CC-1065 elucidated the structural variables responsible for this undesirable hepatotoxicity and culminated in the clinical development of U-71184 and U-73975 at Upjohn. Wierenga, W. Drugs of the Future 1991, 16, 741; Li, et al., Invest. New Drugs 1991, 9, 137: Warpehoski, M. A. Drugs of the Future, 1991, 16, 131; Li, et al., Invest. New Drugs 1987, 5, 329; Warpehoski, et al., J. Med. Chem. 1988, 31, 590; Wierenga, et al., Adv. Enzyme Regul. 1986, 25, 141; Warpehoski, M. A. Tetrahedron Lett. 1986, 27, 4103. Kyowa Hakko Kogyo has since initiated an effort in the fermentation of molecules in this class and has isolated a number of natural products with very promising pharmacology. Ichimura, et al., J. Antibiot. 1990, 43, 1037; Ishii, et al., J. Antibiot., 1989, 43, 1713; Ogawa, et al., J. Antibiot. 1989, 42, 1299; Ohba, et al., J. Antibiot. 1988, 41, 1515.
This invention provides novel furanoindoline compounds effective in inhibiting the growth of solid tumors.